Inflammation is a local and protective response to tissure injury and destruction of cells. The precise elements constituting the inflammatory response vary according to the site of injury, the state of the body, and the injurious agent, such as bacteria or trauma. Should the inflammatory response become impaired or compromised, however, the corresponding tissue will undergo a degenerative process stimulating further injury and cell destruction. Obviously, then, the inflammatory response embodies a multifaceted process that is required to promote and rehabilitate normal tissue function. Therefore, since the inflammatory response is generally similar with various stimuli, it can be viewed and treated as a relatively nonspecific response.
Inflammation may be manifested in numerous ways and one of the more well-known forms is arthritis. By definition, arthritis constitutes inflammation of a joint. Unfortunately, approximately 14% of the present United States population suffers from some type of arthritic manifestations. Further, if arthritis is ineffectively treated, it can develop into an extremely painful, degenerative and crippling disease. The present anti-arthritic therapy constitutes painful, toxic, inconvenient and ineffective protocols designed primarily to alleviate the symptoms rather than the causes. Thus, in light of current knowledge and the notorious effects of arthritis, there obviously is a critical need to develop an effective, safe, painless and convenient form of treatment that can be employed to alleviate successfully the causes of arthritic inflammation.
Today, methods of treating inflammation or arthritis with metals such as copper are well established. For instance, it has been known since ancient Egypt that copper has been indicated for therapeutically treating granulomatous inflammation. In a another instance, it has been established that the dissolution of copper from copper jewelry, for example, bracelets, worn in contact with skin appears to have therapeutic anti-inflammatory effects. Whitehouse, M. W. and Walter, W. R.: The Copper Bracelet for Arthritis. Med. J. Australia. (1):938 June 18, 1977. In still another instance, subdermal copper implants in rats have been demonstrated to exhibit anti-inflammatory activity. In a further instance, a neutral copper (II) bis(glycine) complex perfused through cat skin demonstrating that skin is permeable to soluble copper. In still a further instance several oral and parenteral copper complexes have been somewhat successfully used in the treatment of inflammation or arthritis. Such examples include penicillamine, Cu(II)salicylate, Cu(II).sub.2 (aspirinate).sub.4 and Cu(II).sub.2 (acetate).sub.4. Sorenson, J. R. J.: Development of Copper Complexes for Potential Therapeutic Use. Agents and Actions. Vol. 8 Supplement, pp. 305 at 307-310, 1981. Finally, dermally applied copper complexes have been confirmed as pharmacoactive anti-inflammatory agents. Walker et al: Dermal Copper Drugs: A Copper Bracelet and Cu(II) Salicylate Complexes. Agents and Actions. Vol. 8 Supplement pp. 359-367, 1981. Unfortunately, the current copper-containing dosage forms have been somewhat ineffective as a means to maximize delivery of copper to the strategic inflammatory or arthritic sites.
As with most other therapeutics, the precise mechanism of activity and, indeed the pertinence of copper per se to therapeutic use in inflammatory or arthritic conditions are somewhat hypothetical. However, there have been suggested in the literature several plausible biochemical mechanisms of action that are responsible for the anti-inflammatory or antiarthritic activity exhibited by copper complexes, and those are incorporated herein. Sorenson, J. R. J.: Development of Copper Complexes for Potential Therapeutic Use. Agents and Actions. Vol. 8 Supplement, pp. 305, at 313, 1981. With respect to the importance of copper as a therapeutic agent in arthritic conditions, there is an abundancy of significant evidence. For example, penicillamine, an oral potent copper complexing agent, exhibits effective anti-inflammatory action in arthritis. Lengfelder, E. and Elstner, E. F. (Munich): Determination of the Superoxide Dismutating Activity of D-penicillamine Copper. Hoppe-Seyler's Z. Physiol. Chem. 59:751-757, June 1978. Collagen and elastin cross linkages are poorly formed, if at all, in copper deficiency resulting in weakened tissues. Chou, W. S., Savage, J. E. and O'Dell, B. L. (Columbia, MO): Relation of Monoamine Oxidase Activity and Collagen Crosslinking in Copper-deficient and Control Tissues. Proc. Soc. Exp. Biol. Med. 128:948-952, August-September 1968. Reduced superoxide dismutase (SOD), a copper dependent enzyme, in the leukocytes of patients with rheumatoid arthritis leads to the induction of degenerative changes. Scudder, P., Stocks, J. and Dormandy, T. L. (London): The Relationship between Erythrocyte Superoxide Dismutase and Erythrocyte Copper Levels in Normal Subjects and in Patients with Rheumatoid Arthritis. Clin. Chim Acta 69:397-403, June 15, 1976. Various chelates have demonstrated superoxide dismutasic activity including copper penicillamine, copper salicylate, copper acetylsalicylate and copper-para- aminosalicylate. Younes, M. and Weser, U. (Tubingen): Reactivity of Superoxide Dismutase-active Cu(II) Complexes on the Rate of Adrenochrome Formation. FEBS Lett. 71:87-90, Nov. 15, 1976. Copper amino acid compounds exhibit similar activities; e.g., copper tyrosine and copper lysine. Joester, K.-E., Jung, G., Weber, U. and Weser, U. (Tubingen): Superoxide Dismutase Activity of Cu.sup.2+ -amino Acid Chelates. FEBS Lett. 25:25-28, Sept. 1, 1972. On the other hand, diethyldithiocarbamate, a very potent copper chelant, inhibits superoxide dismutase in cell cultures, presumably by leaching the SOD copper. The SOD activity is restored by replacing the copper. Lin, P. S., Kwock, L. and Goodchild, N. T. (Boston): Copper Superoxide Radical, Diethyldithiocarbamate, and Bleomycin Cytotoxicity (Letter to editor): Lancet 1:777, Apr. 7, 1979. In human fibroblasts there is a production of free radical oxygen which is accompanied by a parallel rise in the concentration of cytoplasmic superoxide dismutase and correlates in the deterioration and aging of cell populations. Oberley, J. W., Oberley, T. D. and Buettner, G. R. (Iowa City): Cell Differentiation, Aging and Cancer: The Possible Roles of Superoxide and Superoxide Dismutases. Med. Hypoth. 6:249-268, March 1980; Somville, M. and Remacle, J. (Namur): Superoxide Dismutases in Aging Fibroblasts. Arch. Int. Physiol. Biochim. 88:B99-B100, May 1980. Orgotein, a copper-zinc protein which exhibits superoxide dismutase activity, has been used therapeutically in patients with rheumatoid arthritis and has been found to be as effective as gold or penicillamine. Menander-Huber, K. B. and Huber, W. (Mountain View, CA): Orgotein, the Drug Version of Bovine Cu-Zn Superoxide Dismutase. II. A Summary Account of Clinical Trials in Man and Animals. In: Michelson, A. M., McCord, J. M. and Fridovich, I. (Eds): Superoxide and Superoxide Dismutases. London:Academic Press, 1977. pp. 537-549. Further, the formation of Cu-cuprizone complex is prevented in the urine of 80% of rheumatoid arthritis patients and in only 5% of the "normal" population. Gerber, D. A. (New York): Increased Copper Ligand Reactivity in the Urine of Patients with Rheumatoid Arthritis. Arthritis Rheum. 9:795-803, December 1966. Finally, it has been observed that copper containing components in the blood increase in patients with rheumatoid arthritis and other degenerative diseases. This evidence patently demonstrates that copper is pharmacoactive and plays a key role in maintaining as well as repairing tissues to facilitate remission of inflammatory diseases. Thus, the prior art, as a whole, verifies that copper in the blood is vital as a "putative modulator" of inflammation. Sorenson, J. R. J.: Development of Copper Complexes for Potential Therapeutic Use. Agents and Actions. Vol. 8 Supplement, pp. 305-325, 1981.
Presently, conventional anti-inflammatory therapy includes application of heat, exercise, salicylates to tolerance, indomethacin or butazolidin, and oral and intraarticular steroids. The above anti-inflammatory protocol, however, is less than optimum because it provides only a means to inhibit some component of the inflammatory process in a generally temporary or transient fashion. In other words, it treats the symptoms rather than promoting tissue repair or alleviating the causes of the degeneration. Sorenson, J. R. J.: The Anti-Inflammatory Activities of Copper Complexes. Metal Ions in Biological Systems. IN: Helmut, S. (Ed): Inorganic Drugs in Deficiency and Disease. Vol. 14 New York: Marcel Dekker, Inc. p. 78 (1982).
In other instances of anti-inflammatory therapy, various prior art approaches have been taken to employ copper as a means to directly alleviate the causes of inflammation and to promote tissue repair. These have led to several improved copper compositions and dosage forms in an effort to maximize delivery of copper to the inflammatory areas. Representative of prior art literature in this area are Sorenson, J. R. J.: Development of Copper Complexes for Potential Therapeutic Use. Agents and Actions. Vol. 8 Supplement, pp. 305-325, (1981). Such literature and efforts of others in substance have been directed to overcoming the present ineffective and inconvenient treatment of inflammation or arthritis with copper. In substance, in such prior art processes, there are apparently four dosage forms made available that incorporate copper. Such dosage forms include parenteral (subcutaneous, intravascular, or intramuscular injection), oral, topical or inserts. The parenteral copper dosage forms are obviously painful, inconvenient, require the presence of a physician, and cause further irritation at the site of injection. The oral dosage forms, on the other hand, are poorly absorbed by the gastric lining, reducing their anti-inflammatory activity. There are several factors known, however, that can be attributed to their poor absorption upon oral ingestion. In one instance, gastric acidity contributes to the possible destruction of the oral copper-containing complexes. In another instance, the use of ionic suspending agents, e.g., tragacanth and acacia, can either sequester the copper ions from these complexes or form quaternary complexes. Finally, single oral doses are poorly absorbed probably for the reasons stated above. With respect to the copper inserts, they too are painful, require a physician to be inserted, and can be intentionally or accidentally removed. Finally, the topical copper dosage forms are commonly used when selecting a route in medicating inflammation or arthritis, as disclosed above. The administration of such topical dosage forms are patently desirable because of their unique and advantageous characteristics. Notwithstanding the notoriety for topical dosage forms, the past and present topical copper complexes have not performed to their anticipated expectations as a means to effectively and conveniently treat inflammation or arthritis with copper. For example, the application of metal salts to proteinaceous membranes, such as skin, results in the attachment of the copper ions to the membrane components to form copper proteinates or salts. Thus, little if any copper ion, in the soluble, ionized state is ever introduced into the targeted inflammatory or athritic areas. Further, copper salts can be corrosive to the skin possibly causing the patient to incur various types of lytic reactions. To overcome this undesirable characteristic, copper ions are complexed with a ligand or chelant to form a metal complex. In other words, the copper is shielded from binding to the membrane components. An example of such topical complexes include copper-amine complexes and copper EDTA. Unfortunately, there are undesirable characteristics associated with these complexes which obviate their usefulness. For example, these highly stable copper complexes are capable of traversing the membranes, but because the copper ions are so very tightly bound to the complex and/or shielded from the copper acceptor sites, the copper ions are essentially unavailable to perform any useful therapeutic function. Moreover, when salicylates are used as the ligands additional problems can be incurred, particularly if used in patients or animals with allergies to salicylates. Regarding topical treatment with copper jewelry, copper absorption is dependent upon dissolution of copper from the jewelry by the bearer's sweat. Thus, predetermined therapeutic amounts of copper cannot be reliably delivered to the targeted inflammatory or arthritic areas. Further, an undesirable green ring or mark is often left on the bearer's skin that is associated with copper jewelry use.
It is apparent from the above brief overview of the importance of copper to inflammation or arthritis and the current state of knowledge that there are critical needs that must be met and problems to be solved, so that inflammation or arthritis may be more effectively and conveniently treated.